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Everolimus dosing recommendations for tuberous sclerosis complex-associated refractory seizures.


ABSTRACT:

Objective

The present analysis examined the exposure-response relationship by means of the predose everolimus concentration (Cmin ) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target Cmin range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target Cmin .

Methods

A model-based approach was used to predict patients' daily Cmin . Time-normalized Cmin (TN-Cmin ) was calculated as the average predicted Cmin in a time interval. TN-Cmin was used to link exposure to efficacy and safety end points via model-based approaches. A conditional logistic regression stratified by age subgroup was used to estimate the probability of response in relation to exposure. A multiplicative linear regression model was used to estimate the exposure-response relationship for seizure frequency (SF). An extended Cox regression model was used to link exposure to the time to first adverse event.

Results

There was a strong, consistent, and highly significant relationship between everolimus exposure and efficacy, measured by TN-Cmin and SF, regardless of patient's age and concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors/inducers. Results of an extended Cox regression analyses indicated that twofold increases in TN-Cmin were not associated with statistically significant increases in the risk of stomatitis or infections.

Significance

The recommended TDM is to target everolimus Cmin within a range of 5-7 ng/mL initially and 5-15 ng/mL in the event of an inadequate clinical response, and safety is consistent with previous reports. Starting doses depend on age and the concomitant use of CYP3A4/P-glycoprotein inducers/inhibitors.

SUBMITTER: Franz DN 

PROVIDER: S-EPMC6033043 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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<h4>Objective</h4>The present analysis examined the exposure-response relationship by means of the predose everolimus concentration (C<sub>min</sub> ) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target C<sub>min</sub> range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target C<sub>min</sub> .<h4>Methods</h4>A model-based approach was used to pre  ...[more]

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